Clinical assessment of T2 papillary thyroid carcinoma: a retrospective study conducted at a single tertiary institution

The extent of surgery among patients with T2 papillary thyroid carcinoma (PTC) remains controversial. Thus, we herein aimed to evaluate the risk factors for recurrence, particularly based on the extent of surgery, among patients with T2 PTC at a single tertiary institution. We assessed 251 patients who underwent thyroid surgery for T2 PTC from January 2009 to December 2014 at Seoul St. Mary’s Hospital (Seoul, Korea). The mean follow-up duration was 100.7 months. Eleven (4.4%) patients had recurrence. The recurrence rates did not significantly differ in terms of the extent of surgery (p = 0.868). Patients with a high lymph node ratio (LNR) had a significantly higher recurrence rate than those with a low LNR (p < 0.001). According to a recurrence pattern analysis, five of six patients in the lobectomy group had recurrence in the ipsilateral lateral compartment. A multivariate analysis revealed that a high LNR was a significant risk factor for recurrence (hazard ratio: 11.025, p = 0.002). Our results suggest that patients without clinical evidence of any lymph node metastases and those with limited lesions in the thyroid gland can undergo lobectomy and LNR can serve as an independent risk factor for predicting recurrence in T2 PTC.

tistically significant difference in terms of the extent of surgery between the two groups. The female group had a higher multifocality and bilaterality than the male group (p = 0.001 and p = 0.005, respectively). Meanwhile, the proportion of patients with positive LNs was significantly higher in the male group than in the female group (p = 0.006). However, there was no significant difference in terms of recurrence rates between the two groups (5.0% vs. 4.1%, p = 0.748).
As shown in Table 3, patients were divided into two groups according to tumor size: small tumor group (≤ 3 cm, n = 190 [75.7%]) and large tumor group (> 3 cm, n = 61 [24.3%]). Nevertheless, the two groups did not significantly differ in terms of age, extent of surgery, bilaterality, lymphatic invasion, perineural invasion, BRAF positivity, number of harvested LNs and positive LNs, and TNM stage. The large tumor group had a higher proportion of male patients than the small tumor group (28.4% vs. 42.6%, p = 0.042). The large tumor group had a significantly higher N stage than the small tumor group (p = 0.039). In addition, vascular invasion was more common in the large tumor group than in the small tumor group (4.7% vs. 13.1%, p = 0.037). However, there was no significant difference in terms of recurrence rate between the two groups (3.2% vs. 8.2%, p = 0.142). Table 4 depicts the baseline clinicopathological characteristics according to age. The following groups were divided according to age: younger group (< 55 years, n = 199 [79.3%]) and older group (≥ 55 years, n = 52 [20.7%]). The younger group had a significantly higher proportion of patients with lymphatic invasion, BRAF positivity, and a greater number of harvested LNs and positive LNs than the older group (p = 0.004, p = 0.031, p = 0.042, and p = 0.021, respectively). The younger group had a significantly higher N stage than the older group (p = 0.009). However, the recurrence rates between the two groups did not significantly differ (5.0% vs. 1.9%, p = 0.468). Table 5 shows the baseline clinicopathological characteristics according to LNR. The optimal cutoff for LNR (0.32) was obtained via a receiver operating characteristic (ROC) curve analysis ( Supplementary Fig. 1  . There were no statistically significant differences in terms of extent of surgery, tumor size, bilaterality, vascular and perineural invasion, BRAF positivity, and number of harvested LNs. The high LNR group was significantly younger than the low LNR group (p = 0.006). The proportion of male patients and those with minimal ETE, lymphatic invasion, and positive LNs was higher in the high LNR group than in the low LNR group (p = 0.005, p = 0.001, p < 0.001, and p < 0.001, respectively). The high LNR group had a higher N and TNM stage than the low LNR group (p < 0.001 and p = 0.033, respectively). Moreover, the recurrence rate was significantly higher in the high LNR group than in the low LNR group (1.1% vs. 12.0%, p < 0.001).
Recurrence patterns in the study population. Table 6 shows the recurrence patterns in the study population. Five patients in the lobectomy group had recurrence at the ipsilateral lateral compartment. Only one patient developed recurrence at the contralateral thyroid gland. By contrast, patients in the TT group presented with different recurrence patterns, which are as follows: patient no. 1 at the bilateral lateral compartment, patient no. 2 at the ipsilateral lateral compartment, patient no. 3 at the ipsilateral OP bed, patient no. 4 at the ipsilateral central compartment, and patient no. 5 at the contralateral lateral compartment. In the Kaplan-Meier analysis, DFS differed significantly between the high and low LNR groups (log-rank test, p < 0.001; Fig. 1). However, there was no statistically significant difference in terms of DFS between the TT and lobectomy groups (log-rank test, p = 0.877; Fig. 2).

Discussion
The American Joint Committee on Cancer/Union for International Cancer Control TNM staging system for thyroid cancer defines T category as follows: T0, no evidence of primary tumor; T1, size of ≤ 2 cm and intrathyroidal; T2, 2 cm < size ≤ 4 cm and intrathyroidal; T3, size of > 4 cm or ETE (sternohyoid, sternothyroid, thyrohyoid, and omohyoid muscle); T4, others-gross ETE. T2 accounts for only 3%-13% of all PTC cases in Korea [14][15][16] . The incidence of T1 PTC has increased due to improvements in diagnostic modalities and early screening in Table 4. Baseline clinicopathological characteristics according to age. Data were expressed as number (%) or mean ± standard deviation. A statistically significant difference was defined as p < 0.05. TT total thyroidectomy, mRND modified radical neck dissection, ETE extrathyroidal extension, LN lymph node, T tumor, N node, M metastasis. According to the ATA management guidelines, lobectomy alone may be sufficient when used as an initial treatment for patients with PTC measuring 1-4 cm but without ETE and clinical evidence of any LN metastases 10 . However, the extent of surgery for PTC measuring 1-4 cm is still controversial. After the publication of the 2015 ATA management guidelines, several studies investigated the extent of surgery in PTC measuring 1-4 cm 19-21 . Rajjoub et al. showed that lobectomy is not sufficient for T2 PTC. Results showed that 33,816 adults with conventional PTC measuring 1.0-3.9 cm had a better survival after TT than after lobectomy. This finding was observed particularly in patients with a tumor size of 2.0-3.9 cm 19 . Suman et al. revealed that lobectomy had a significantly negative effect on long-term survival. The exclusion of high-risk features is important when adopting lobectomy Table 5. Baseline clinicopathological characteristics according to lymph node ratio. Data were expressed as number (%) or mean ± standard deviation. A statistically significant difference was defined as p < 0.05. LNR lymph node ratio, TT total thyroidectomy, mRND modified radical neck dissection, ETE extrathyroidal extension, LN lymph node, T tumor, N node, M metastasis.  www.nature.com/scientificreports/ as the definitive surgical therapy for T1b and T2 PTC because of its potential adverse effects on long-term survival 22 . By contrast, previous research revealed that lobectomy might be appropriate for patients with low-risk differentiated thyroid carcinoma (DTC). Cautious risk evaluation and stratification can individualize treatment, prevent overtreatment, and guarantee a good long-term prognosis with a low-risk of recurrence 23 . Filippo et al. revealed no significant difference in terms of the risk of locoregional recurrence or distant metastasis between the TT and lobectomy groups who presented with pT1-T2 and pN0 PTC. Furthermore, compared with lobectomy, TT was correlated with more complications, which included postoperative hypoparathyroidism and recurrent laryngeal nerve injury 20 . Consistent with the study of Filippo, there was no statistically significant difference in terms of recurrence rate between the TT and lobectomy groups in our study (p = 0.868). The Kaplan-Meier analysis of DFS showed no significant difference between the two groups (log-rank test, p = 0.877). If recurrence occurs commonly in the remnant thyroid gland, TT, rather than lobectomy, might be recommended. We analyzed the recurrence patterns in the study population. In the current study, five (4.6%) patients in the TT group and 6 (4.2%) in the lobectomy group were diagnosed with recurrence. All but one patient in the lobectomy group had recurrence at the ipsilateral lateral compartment. On the contrary, the recurrence pattern of the TT group varied. Thus, recurrence occurred mainly in the lateral compartment rather than the remnant thyroid gland after lobectomy.
TT is advantageous as it can improve surveillance accuracy using serum thyroglobulin as a sensitive postoperative marker for residual or recurrent thyroid cancer 24 . Moreover, it allows the use of RAI, which can be used in both postoperative treatment and surveillance 25 . RAI increases the survival rates of patients with intermittent-and high-risk DTC. However, the ATA management guidelines do not recommend RAI ablation in patients with low-risk T2 PTC 10 . Schvartz et al. showed that RAI after surgery has no survival benefit in a large cohort of patients with low-risk DTC 26 .
The extent of surgery should not be based on the risk of recurrence alone. TT can cause various postoperative complications. However, such complications are rare. First, TT is associated with a higher risk of Table 7. Univariate and multivariate analyses of disease-free survival. Data were expressed as hazard ratio (HR) and 95% confidence interval (CI). A statistically significant difference was defined as p < 0.05. ETE extrathyroidal extension, LN lymph node, LNR lymph node ratio.  27 . Permanent hypoparathyroidism is associated with multiple complications, including renal function impairment, gastrointestinal and neuropsychiatric problems, and infections 28 . Second, TT is also associated with a greater risk of recurrent laryngeal nerve injury. Approximately 0.5%-5% and 1%-30% of patients who undergo TT had permanent recurrent laryngeal nerve injury and temporary injury, respectively 29 . Third, patients with PTC are relatively young, mostly in their 40 s or 50 s at the time of diagnosis 30 .
Considering that PTC has a good prognosis, patients must be treated with levothyroxine for about 30-50 years after TT. The long-term use of this drug causes complications including osteoporosis and arrhythmias 31,32 . Further studies about the complications of TT, which were not included in the current study, should be performed.
Since the purpose of this study was to observe the general characteristics of patients with T2 PTC, data on patients' complications were not initially included. Among the patients included in this study, transient vocal cord palsy was observed in three patients (2.1%) in the lobectomy group and four patients (3.7%) in the TT group. There was no statistically significant difference in terms of transient vocal cord palsy between the two groups. Permanent vocal cord palsy was not observed in any patient in the lobectomy group, whereas it was observed in one (0.9%) patient in the TT group. Transient hypoparathyroidism was not found in the lobectomy group, whereas it occurred in 25 patients (23.1%) in the TT group. These findings are consistent with those reported in a recent meta-analysis 33 .
LNR is calculated by dividing the number of positive LNs by the number of harvested LNs, and it is used in predicting recurrence in other types of cancers 34,35 . Recently, LNR was found to be an important predictor of DFS in PTC 36 . Schneider et al. assessed 10,955 cases, and results showed that LNR was a strong prognostic factor 37 . Vas Nunes et al. conducted a retrospective analysis of 198 patients with PTC who underwent TT. Results showed that LNR was an important independent prognostic factor in PTC, and it could be used in combination with existing staging systems 38 . Our study found similar results. An ROC curve analysis was performed to obtain an optimal cutoff value of 0.32. A multivariate analysis found that an LNR of > 0.32 was a significant risk factor for recurrence. In the Kaplan-Meier analysis, the DFS between the high and low LNR groups did not significantly differ (log-rank test, p < 0.001). However, the optimal cutoff of LNR for the risk of recurrence in PTC is still controversial. Schneider et al. showed that a cutoff value of 0.42 can be used for risk stratification in patients with positive LNs 37 . Vas Nunes et al. proposed that an LNR cutoff value of 0.3 can be a prognostic factor 38 . In this study, the optimal cutoff value of LNR was 0.32. Thus, further prospective or multicenter studies must be conducted to determine the optimal cutoff value of LNR. The high LNR group was younger and had a higher number of male patients than the low LNR group. This result was consistent with that of several studies. Wang et al. showed that younger patients with a high LNR are at a greater risk for PTC 39 . Kim et al. performed a large cohort study. Results showed that male patients had a greater number of positive LNs 40 . Nevertheless, further studies should be conducted to determine the relevance of age and sex to LNR. This study identified the recurrence patterns of patients with T2 PTC. Most recurrences did not occur in the remnant thyroid gland after lobectomy. Even though postoperative pathologic results showed that patients had a high LNR, we do not routinely recommend thyroidectomy after lobectomy. Short-term follow-up may be helpful for patients with T2 PTC who have a high LNR after lobectomy.
The current study had several limitations due to its retrospective nature. First, the strength of the result was undermined. Second, the participants were from a single tertiary institution. Hence, this might have caused www.nature.com/scientificreports/ selection bias, and these participants might not reflect the entire patient population. Finally, the follow-up period was relatively short (100.7 ± 18.3 months). Hence, a longer follow-up is required to predict the long-term surgical outcomes of patients with T2 PTC, as it has indolent features. Nevertheless, these limitations could be addressed by conducting a multicenter study in the future. However, the study also had some advantages. That is, each patient was followed-up, and standardized laboratory and imaging protocols from a single institution were used. To the best of our knowledge, only few studies have analyzed T2 PTC individually. Although other studies have already addressed PTC recurrence, this research differs as it has identified recurrence patterns in the TT and lobectomy groups. This then contributes to determining the extent of surgery.
In conclusion, lobectomy is not associated with a higher risk of recurrence and is feasible among patients with T2 PTC. Moreover, it may be considered for patients without ETE, suspicious LN metastasis, and intrathyroidal lesion. LNR can be an independent risk factor for recurrence in T2 PTC. Thus, short-term follow-up may be recommended for patients with T2 PTC who have a high LNR. Postoperative management and follow-up. All patients with T2 PTC were managed after surgical treatment according to the ATA management guidelines 10 . Patients were treated with levothyroxine at suppressive doses and were regularly followed-up. In addition, all patients underwent physical examination, thyroid function test, thyroglobulin (Tg), anti-Tg antibody concentration assessment, and neck ultrasonography every 3-6 months, and annually thereafter. Postoperative RAI ablation was performed at 6-8 weeks after surgery, and whole-body scans were performed at 5-7 days after RAI ablation in patients who underwent TT. To determine the location and extent of suspected recurrence, patients who had evidence of recurrence on routine follow-up evaluations were assessed via additional diagnostic imaging techniques, including computed tomography (CT), positron emission tomography/computed tomography, and/or RAI whole-body scanning. During the follow-up, patients were considered to have recurrent disease if either or both of the following were observed: (1) positive imaging findings on ultrasound-guided needle aspiration biopsy, CT, or diagnostic 131 I whole-body scan and (2) significant increases (i.e. ≥ 50%) in the stimulated and/or basal serum Tg levels with respect to the previous visit(s) 41 . Recurrence was confirmed via histologic examination using ultrasound-guided needle aspiration biopsy or surgical biopsy. Statistical analysis. Continuous variables were presented as mean with standard deviation, and categorical variables as number with percentage. The student's t-test was used to compare continuous variables. Meanwhile, categorical variables were compared using the Pearson's chi-square test or the Fisher's exact test. To determine the optimal cutoff value of the lymph node ratio (LNR), which is defined as the number of positive LNs divided by the total number of LNs harvested, ROC curve analysis was performed. Univariate and multivariate Cox regression analyses were performed to identify the predictors of DFS, which is defined as the length of time for which the patient survives without any signs or symptoms of the cancer after the completion of the primary treatment for the cancer, using calculated HRs with 95% confidence intervals. Kaplan-Meier survival analysis with log-rank test was performed to compare DFS. A p-value of < 0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences software for Windows version 23.0 (IBM Corp., Armonk, NY, USA).

Data availability
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.